Multi-targeting Peptide-Functionalized Nanoparticles Recognized Vasculogenic Mimicry, Tumor Neovasculature, and Glioma Cells for Enhanced Anti-glioma Therapy

Abstract

Chemotherapy failure of glioma, the most aggressive and devastating cancer, might ascribed to the physiologic barriers of the tumor mainly including heterogeneous tumor perfusion and vascular permeability, which result in a limited penetration of chemotherapeutics. Besides, the vasculogenic mimicry (VM) channels, which is highly resistant to the antiangiogenic therapy and serves as a complement of angiogenesis, was abound in glioma and always associated with tumor recurrence. In order to enhance the therapy effect of anti-glioma, we developed a PEG-PLA-based nano-drug delivery system (nanoparticles, NP) in this study and modified on its surface with CK peptide, which was composed of a human sonic hedgehog (SHH) targeting peptide (CVNHPAFAC) and a KDR targeting peptide (K237) through a GYG linker, for facilitating an efficient VM channels, tumor neovasculature and glioma cells multi-targeting delivery of paclitaxel. In vitro cellular assay showed that CK-NP-PTX not only exhibited the strongest anti-proliferation effect on U87MG cells and HUVEC cells, but also resulted in the most efficient destruction of VM channels when compared with CVNHPAFAC-NP, K237-NP and the unmodified ones. Besides, CK-NP accumulated more selectively at the glioma site as demonstrated by iIn vivo and ex vivo imaging. As expected, the glioma bearing mice treated with CK-NP-PTX achieved the longest median survival time compared with CVNHPAFAC-NP-PTX and K237-NP-PTX. These findings indicated that the multi-targeting therapy mediated by CK peptide might provide a promising way for glioblastoma therapy.